Abstract
Mutations in Lef1 occur in human and mouse sebaceous gland (SG) tumors, but their contribution to carcinogenesis remains unclear. Since Gata6 controls lineage identity in SG, we investigated the link between these two transcription factors. Here, we show that Gata6 is a β‐catenin‐independent transcriptional target of mutant Lef1. During epidermal development, Gata6 is expressed in a subset of Sox9‐positive Lef1‐negative hair follicle progenitors that give rise to the upper SG. Overexpression of Gata6 by in utero lentiviral injection is sufficient to induce ectopic sebaceous gland elements. In mice overexpressing mutant Lef1, Gata6 ablation increases the total number of skin tumors yet decreases the proportion of SG tumors. The increased tumor burden correlates with impaired DNA mismatch repair and decreased expression of Mlh1 and Msh2 genes, defects frequently observed in human sebaceous neoplasia. Gata6 specifically marks human SG tumors and also defines tumors with elements of sebaceous differentiation, including a subset of basal cell carcinomas. Our findings reveal that Gata6 controls sebaceous gland development and cancer.
Highlights
At the core of the canonical Wnt signaling pathway is nuclear translocation of b-catenin and consequent transcription of downstream target genes through b-catenin binding to members of the lymphoid enhancer-binding factor/T-cell factor (Lef/Tcf) transcription factor family (Klaus & Birchmeier, 2008; Nusse & Clevers, 2017)
Gata6 expression in the epidermis is limited to a population of sebaceous ducts (SD)/sebaceous gland (SG) progenitors in the developing hair follicle (HF) and to the junctional zone (JZ), upper SG, and part of the infundibulum in adult skin (Figs 2A and 6A, and EV2A–C; Donati et al, 2017)
Gata6 is strongly upregulated in the epidermis of K14DNLef1 mice (Fig 1H) and is a direct DNLef1 target gene (Fig 1C), we saw no evidence for co-expression of Gata6 and Lef1 in developing or adult epidermis and Gata6 was not induced upon b-catenin activation (Fig 2), even though Gata6 synergizes with or activates Wnt signaling in a number of contexts (Afouda et al, 2008; Zhang et al, 2008b; Whissell et al, 2014)
Summary
At the core of the canonical Wnt signaling pathway is nuclear translocation of b-catenin and consequent transcription of downstream target genes through b-catenin binding to members of the lymphoid enhancer-binding factor/T-cell factor (Lef/Tcf) transcription factor family (Klaus & Birchmeier, 2008; Nusse & Clevers, 2017). The Wnt pathway plays a central role in stem cell maintenance and fate specification in mammalian epidermis (Watt & Collins, 2008; Lim & Nusse, 2012), controlling the balance between hair follicle (HF) and sebaceous gland (SG) differentiation. Ectopic HF can be generated upon transient activation of epidermal b-catenin (Lo Celso et al, 2004; Silva-Vargas et al, 2005), in particular in Lrig1-positive and Lgr6-positive stem cell (SC) populations of the upper pilosebaceous unit (Kretzschmar et al, 2016). While Wnt signaling favors HF over SG fate, an N-terminally truncated form of Lef (DNLef1), unable to bind b-catenin, converts HF into keratinized epidermal cysts with ectopic sebocytes (Merrill et al, 2001; Niemann et al, 2002; Donati et al, 2017). Transgenic mice overexpressing a stabilized form of bcatenin develop HF tumors: pilomatricomas or trichofolliculomas (Gat et al, 1998; Lo Celso et al, 2004). In humans, stabilizing mutations in b-catenin are found in a majority of pilomatricomas (Chan et al, 1999) and pilomatrix carcinomas (Lazar et al, 2005)
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